Cancer cell quiescence, effectively a cell in a state of sleep, has been recognized recently as a major mechanism of the resistance of cancer cells to treatments and for providing a pathway for disease recurrence. This quiescence, alternatively called cellular dormancy, is due to arrest at G0 phase of the cell cycle. Typically, a cell enters a cell cycle from gap phase 1 (G1), as shown in FIG. 1. After a synthesis phase (S) and a short pre-mitotic interval (G2), the cell divides by mitosis (M) followed by a return to G1. Instead of G1, however, a cell can enter cellular dormancy or quiescence, designated as the G0 phase. Cancer cells can either enter an irreversible state before undergoing terminal differentiation, termed senescence, or enter a reversible, true quiescent G0 state from which they could resume cycling, like quiescent fibroblasts (Coller H A, Sang L, and Roberts J M (2006) A new description of cellular quiescence, PLoS Biology 4, e83).
A population of cells naturally may be in a quiescent state at any given time and remain quiescent for an indeterminate period until receipt of a signal to enter the cell division cycle. In one example, the proportion of cancer cells in quiescent state within a population in a tumor may be increased by environmental factors, such as lack of nutrients, hypoxia, high concentration of reactive oxygen species, etc. Cells may also be induced into the quiescent state by the action of a drug substance, as in pharmacological quiescence.
The energy and nutrient requirements of a quiescent cell are reduced relative to a dividing cell. Since current cancer therapies target dividing cells, as illustrated in FIG. 2, and therefore a cancer cell must be in the cell division cycle for such treatments to affect it. Accordingly, a quiescent cancer cell is resistant to treatments that affect one of more cellular proliferation processes by means of damaging exposed DNA, interfering with DNA replication or repair, interfering with mitosis, or other mechanisms.
Both anticancer therapeutics and radiation treatments produce adverse effects. Consequently, doses and duration of treatment are limited by toxicity and lower effective doses and/or shorter treatment durations are highly desirable. Upon reduction in doses or discontinuation of treatment, however, the surviving quiescent cancer cells can cause cancer recurrence upon re-entry to the cell cycle, the timing of which cannot be predicted. Further, metastatic cancer cells in the bloodstream may experience a period of quiescence while they adapt to their new microenvironment (Chaffer C L and Weinberg R A (2011) A perspective on cancer cell metastasis, Science 331, 1559-1564). Quiescent cancer cells degrade their polyribosomes, thus blocking translation and reducing total RNA and protein content. These shrunk cancer cells may be able to enter the bores of capillaries (approximately 8 μm diameter) whereas cycling cancer cells are usually much larger (20-30 μm).
Accordingly, the existence of a population of quiescent cancer cells within a neoplasm is recognized as an obstacle to successful and durable treatment (Jackson R C (1989) The problem of the quiescent cancer cell, Advances in Enzyme Regulation 29, 27-46). Evidence for resistance of quiescent cancer cells derived from various cancer types and to various anti-cancer treatments has been reported.
Yet, despite a growing appreciation of the importance of cancer cell quiescence, this issue remains unaddressed clinically. Accordingly, the present invention provides methods and combinations for the treatment of neoplasms that features the targeting of quiescent cancers cells by small molecules, particularly molecules effective against quiescent cancer cells, in combination with treatments known to be effective against certain neoplastic cells.